This project will apply whole genome sequencing (WGS) to comprehensively identify the genetic variants contributing to the risk of severe bipolar disorder (BP-I) in an exceptionally well characterized set of extended pedigrees. BP is a common, severe psychiatric syndrome, which is highly heritable yet etiologically heterogeneous. Our collaborative team is already funded to conduct extensive phenotyping (for both the BP-I diagnosis and for quantitative measures that assay the biology underlying BP, i.e. endophenotypes) and genome wide linkage and association analyses based on dense SNP genotyping in 850 individuals in 26 pedigrees. These pedigrees, each with multiple BP-I affected individuals, are drawn from the related population isolates of the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). We now propose to conduct deep WGS in 450 individuals from these families; the WGS data will be used to impute comprehensive genome wide variation in the entire set of genotyped individuals. Statistical and bioinformatic analyses will be undertaken to prioritize for replication in independent study samples the variants most likely to be contributing to BP-I or BP-related endophenotypes. The data from this project will be shared rapidly with the scientific community, providing a unique resource for efforts aimed at a better understanding, treatment, and prevention of mental disorders. PUBLIC HEALTH RELEVANCE: Traditional strategies have not succeeded in dissecting the genetic basis of bipolar disorder (BP), a devastating, common, and highly heritable psychiatric syndrome. This project will sequence the whole genomes of members of pedigrees that each include many individuals affected with severe bipolar disorder (BP-I). By comprehensively identifying the genetic variation that could contribute to BP-I in these pedigrees, the project wil advance the understanding, treatment, and prevention of severe mental disorders.